ES2203373T3 - PROCEDURE TO PREPARE (1R, 2S, 4R) - (-) - 2 - ((2 '- (N, N-DIMETHYLAMINE) -ETOXI)) - 2- (PHENYL) -1,7,7-TRI- (METIL ) -BIKE (2.2.1) HEPTAN AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS OF THE SAME. - Google Patents

Abstract

Preparation procedure for (1R, 2S, 4R) - (-) - 2 - [(2¿- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1, 7, 7-thicyclo [2.2 .1] heptane of formula I and the pharmaceutically acceptable acid addition salts thereof by converting (+) - 1, 7, 7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula II by reacting the first with a phenyl magnesium halide or phenyl alkali compound, if necessary by carrying out the hydrolysis of the reaction product, and reacting (1R, 2S, 4R) - (-) - 2- [ phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III obtained in this way with (2- {halogen} -ethyl) -dimethylamine in the presence of a hydride alkali metal or alkali metal amide in an organic solvent and, if desired, converting the base (1R, 2S, 4R) - (-) - 2 - [(2¿- {N, N-dimethylamino} -ethoxy) ] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I obtained in this way in a salt, characterized by carrying out the reaction of (1R, 2S, 4R) - (-) - 2- [phenyl] -1, 7, 7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III and (2- {halogen} -ethyl ) -dimethylamine in a medium containing 1 or more compounds with a saturated 5- or 6-membered heterocyclic ring with 2 annular oxygen atoms as solvent or solvents.

Description

Procedure to prepare (1R, 2S, 4R) - (-) - 2 - [(2 '- (N, N-dimethylamino) -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane and pharmaceutically acceptable acid addition salts of the same.

The invention relates to a method for prepare (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane and pharmaceutically acceptable acid addition salts of same.

Salt 2- (E) -butanedioate (1: 1) fumarate of (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula

one

it is an anxiolytic active ingredient known to the INN of "fumarate of deramciclano ".

The compound of formula I is classified within General Formula I of Hungarian Patent No. 179,164 (= GB 2,065 122A) but has not been disclosed exactly and explicitly in this patent specification, nor has the preparation of the same. According to Hungarian Patent No. 179,164, ethers cycloalkyl amine alkanol of its general formula I are prepared reacting (+) - 1,7,7-Tri- [methyl] -bicyclo [2.2.1] heptane-2-one, that is, (+) - formula camphor

two

with the organo-metallic compound corresponding, subjecting the compound obtained to hydrolysis and introducing into the hydroxy group of the product obtained, the chain basic side by etherification. As compound organo-metallic, a compound of Grignard or an organic alkali metal compound, preferably a lithium compound or of sodium.

The preparation of the compound of formula I is given to know exactly in Hungarian Patent No. 212,574 (= HU 60 996 A, with reference in CHEMICAL ABSTRACTS, vol. 118, nº 23, June 7 1993, summary No. 234291c). The essence of this procedure is that product purification is carried out at a later stage of synthesis According to the procedure, it is submitted to (+) - camphor of formula II to Grignard reaction with Phenyl magnesium bromide in diethyl ether, providing (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula

3

with a yield of 28% (according to the CG). The compound (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III is in the reaction mixture and is not insulate The complex decomposes, the reaction mixture is converts, without purification, into sodium salt by reaction with sodium amide or sodium hydride, and the sodium salt obtained is made react with anhydrous 2- {chloro} -ethyl) -dimethylamine in toluene medium. The reaction mixture contains, in addition to the base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I (present in an amount of 20 to 30%), an amount considerable impurities and starting products, for example (+) - unreacted formula II camphor, (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane-2-ol, 1,7,7-tri- [methyl] -bicyclo [2.2.1] beptane-2-ol and impurities biphenyl, triphenyl, etc. Base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N- dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I is separated from said contaminants by extraction with aqueous tartaric acid, by which the base is released and the fumarate salt The total amount of (+) - camphor of unreacted formula II and of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III is in the organic phase of the extractive stage of tartaric acid, which can be reused in the reaction of Grignard after removing the solvent and water (that is, it can recirculate towards the process). In this way, it can be used in more efficient way the (+) - camphor; without recirculation, only 16% by weight approximately (+) - used camphor can be used, while, in the case of one and three recirculations, this value is increased at 22% and 25% by weight, respectively. In this way, the yields are too small, particularly from the point view of the viability commercial.

It is very important, and it should be emphasized, that a considerable part of the (+) - camphor of formula II used in the Grignard reaction does not react, and this product Starting technically it cannot be removed from the desired product due to the physical properties of (+) - camphor and compound lability (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III formed, since the compound (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol  of formula III is susceptible to decomposition. For this reason, according to the procedure disclosed in the patent Hungarian No. 212,574, the alkylation stage always takes place in presence of (+) - camphor of formula II.

The aforementioned gives rise to drawbacks of the procedure disclosed in the patent Hungarian No. 212,574. The alkali hydrides and amides used in the first stage of the alkylation reaction forms non-salts only with alcohol (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III, but also with the (+) - camphor of formula II and with other compounds containing an active atom of hydrogen present in the reaction mixture. For this reason, apart of the desired compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I, are obtained additional alkylated derivatives that are formed, for example, to starting from (+) - unreacted camphor, and the compound wanted (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I must be recovered of a mixture containing such impurities and also the compounds unreacted (+) - camphor and (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula II and III. Raw compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I can only be purified, although incompletely, by means of recrystallization from dimethyl formamide. However, with the help of such recrystallization can only be completely eliminated non-basic contaminants, which do not form salts.

An additional disadvantage of recrystallization in dimethyl formamide is that traces of the solvent cannot separate from the desired pharmaceutically active principle in the required grade

It has been found that, in the case of the reaction of alkylation of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III carried out with (2- {chloro} -ethyl) -dimethylamine, always being present (+) - camphor of formula II, gives rise to formation of considerable quantities of by-products, for example, (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula

4

The byproduct (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V is formed as follows: under the conditions used in the etherification reaction, the (+) - camphor of formula II forms an alkali salt in position 3 which, in turn, reacts with (2- {chloro} -ethyl) -dimethylamine, used as agent alkylating agent, yielding the compound of formula V. The amount of By-product of formula V can be 1 to 10%. The solubility of fumarate 2- (E) -butanedioate (1: 1) of the compound (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V is approximately identical to that of the fumarate of desired compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I and, therefore, crystallize together with the fumarate of the compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I and contaminate the desired final product. If the etherification is carried out in toluene, as described in the Hungarian Patent No. 212,574, the product obtained after the salt formation in ethanol, contains considerable amounts of the impurity (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V.

Salt is a highly insoluble compound and it can be recrystallized only from dimethyl formamide. Nevertheless, recrystallization from dimethyl formamide does not allow to provide a compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I in a purity as required by the Pharmacopoeias, by following reasons:

to)

The product obtained after recrystallization from dimethyl formamide still contains the compound (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-one of formula V in an amount above the allowed threshold value by the Pharmacopoeia (approximately 0.5%).

b)

Dimethyl formamide has a high boiling point and cannot be separated of the product in the required degree because, at the elevated temperature, Product decomposition takes place.

Could not get a purification to perform products with sufficient purity to prepare medicines from agreement with the Pharmacopoeias, by the usual procedures of purification, such as recrystallization in solvents or fractional distillation.

Taking into account the strict requirements of the Pharmacopoeia, the presence in excessive amounts of impurities can endanger the use of the active substance for purposes Pharmacists Impurity (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-one of formula V can therefore cause problems in the compound use (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I as active ingredient.

In summary, it can be stated that during the purification of (1R, 2S, 4R) - (-) - 2- [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I prepared by the known method, dimethyl formamide would be the only solvent conceivable. However, this method of recrystallization is unsuitable for the preparation of a pharmaceutical ingredient asset that meets the requirements of the Pharmacopoeias, because the dimethyl formamide has a boiling point so high that Traces thereof cannot be removed from the product in grade enough. At the high temperature required, the compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of Formula I is susceptible to decomposition.

As previously disclosed, (+) - camphor of formula II is present during the alkylation reaction. From (+) - camphor, it form, as an additional pollutant, (1R, 4R) -2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 1,7,7-tri- [methyl] - bicyclo [2,2,1] heptane of formula

5

If an alkali metal hydride is used or alkali metal amide as a basic salt forming agent, the amount of contaminant (1R, 4R) -2 - [(2 '- {N, N- dimethylamino} -ethoxy)] - 1,7,7-tri- [methyl] -bicyclo [2,2,1] heptane Formula IV is 1 to 10%. The compound (1R, 4R) -2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 1,7,7-tri- [methyl] - bicyclo [2,2,1] heptane of formula IV is already known in prior art [Yakugaku Zasshi, 75, 1377 (1955); Chem. Abstr. 9340 (1956)]. The compound (1R, 4R) -2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 1,7,7-tri- [methyl] -bicyclo [2,2,1] heptane of Formula IV is formed as follows: metal hydride alkali or alkali metal amide used for the formation of sodium salt in the etherification stage reduces 1 to 10% of the (+) - camphor of formula II to borneol, which is converts, under the reaction conditions used, the salt of alkali metal, and said alkali salt enters a reaction of alkylation together with (2- {chloro} -ethyl) -dimethylamine.  However, borneol ether (1R, 4R) -2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 1,7,7-tri- [methyl] - bicyclo [2,2,1] heptane of formula IV can be separated of the desired compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N- dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I during the course of the development of the mixture of reaction.

The problem underlying the invention is provide a procedure to prepare (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I and pharmaceutically acceptable acid addition salts thereof with a higher degree of purity without the need for stages of recrystallization purification, which, anyway, they would only lead to insufficient purification and reduce performance and, in addition, would have the disadvantage of not the residual solvent could be separated from the final product in grade Enough even by complicated methods.

Also from EP 0 694 299 A, particularly in the page 6, is known (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I and addition salts of acid thereof. There is no indication as to the preparation nor The purity of it. Therefore, obviously the compound of formula I should be considered to have only the aforementioned lower purity as could be obtained at that time.

Surprisingly, the above has been resolved by the present invention.

The present invention is based on the fact surprising that if the reaction between the reaction mixture that contains the compound (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7- tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III and (2- {chloro} -ethyl) -dimethylamine is carried out in presence of an alkali metal hydride or alkali metal amide in a medium containing 1 or more compounds with a ring 5 or 6-membered saturated heterocyclic with 2 oxygen atoms annular as solvent or solvents, in particular dioxane, the reaction is clearly directed in favor of the formation of the desired (1R, 2S, 4R) - (-) - 2 - [(2'- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I, and the byproduct (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V is formed only in a minimum quantity. The fact above allows the preparation of the desired compound (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} - ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I in higher yields and with a degree of purity higher, particularly considering impurity (1R, 3S, 4R) -3- [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-one of formula V. In this way, a compound can be obtained (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I that directly meets the requirements of the Pharmacopoeia in terms of purity and solvent content residual

Throughout the text, the percentages regarding content of the compounds of formulas I and V, and others compounds, are the result of the chromatography analysis of gases, the same being the proportion of the area under the peak in issue and total area under all peaks.

The term "acid addition salts pharmaceutically acceptable "using herein patent specification means salts formed with acids inorganic, for example, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with organic acids, by example, acetic acid, tartaric acid, succinic acid, acid malic, lactic acid, citric acid, maleic acid or acid fumaric Salt formed with fumaric acid has properties particularly useful.

The (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - [2.2.1] heptane of formula I has three centers asymmetric, in positions 1, 2 and 4.

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Therefore, the subject of the invention is a process for preparing (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethyla-
mino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I and the pharmaceutically acceptable acid addition salts thereof by converting (+) - 1,7,7-Tri- [methyl] -bicyclo [2,2,1] heptane-2-one {(+) camphor} of formula

6

in (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol from formula

7

by reacting the first with a halide of phenyl magnesium or phenyl alkali compound, if necessary carrying out the hydrolysis of the reaction product, and doing react (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III obtained in this way, with (2- [halogen] -ethyl) -dimethylamine in presence of an alkali metal hydride or a metal amide alkali in an organic solvent and, if desired, converting the base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I obtained from this way in a salt, characterized by carrying out the reaction of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III and (2- {halogen} -ethyl) -dimethylamine in a medium containing 1 or more compounds with a ring 5 or 6-membered saturated heterocyclic with 2 oxygen atoms annular as solvent or solvents. The invention is not limited to the use of 1 or more compounds with a heterocyclic ring saturated with 5 or 6 members with 2 annular oxygen atoms, such as dioxane, as a solvent only, but also comprises the use of solvents containing at least 50% by weight, preferably 75% by weight, in particular 90% by weight, of 1 or more Compounds with a saturated 5 or 6-membered heroic ring with 2 annular oxygen atoms, such as dioxane

The essential feature of the procedure The present invention is that the alkylation is carried out in a solvent that does not favor the alkylation reaction in position 3 del (+) - camphor of formula II in the presence of a basic salt forming agent. It has been discovered that the compounds with a saturated 5- or 6-membered heterocyclic ring with 2 atoms Oxygen ring, in particular dioxane, can be used advantageously for this purpose.

In particular, it is preferably used as solvent, dioxane. Another example is dioxolane, optionally mixed with dioxane.

Examples of solvents that can be used mixed with 1 or more compounds having a heterocyclic ring saturated with 5 or 6 members with 2 annular oxygen atoms, ethylene glycol dimethyl ether, ethylene glycol ether diethyl, dimethyl of diethylene glycol ether and diethyl glycol ether.

Conveniently, a phenyl halide is used magnesium as an organo-metallic compound in a Grignard reaction. Additional examples are the compounds phenyl alkali, such as phenylthio.

Preferably, it is used as a phenyl halide magnesium, phenyl magnesium bromide. An additional example is the phenyl magnesium chloride.

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Suitably the procedure according to the invention in the manner next:

In the first stage of the process of the present invention, (+) - camphor of formula II is subjected to Grignard reaction with, for example, phenyl magnesium bromide. The reaction is carried out in a manner known per se . As the reaction medium, tetrahydrofuran may preferably be used. Phenyl magnesium bromide can be used in an amount of 1 to 3 moles, preferably about 1.5 moles, relative to 1 mole of (+) -camphor of formula II. Preferably, the Grignard reagent can be preferably prepared first from magnesium and bromine benzene in the solvent used and then the solution is added to the (+) - camphor of formula II in an organic solvent at the boiling point of the reaction mixture. It is preferable to use the same solvent to prepare the Grignard reagent and dissolve the (+) - camphor of formula II. Tetrahydrofuran can be advantageously used as a solvent. The reaction is advantageously carried out at the boiling point of the reaction mixture.

The mixture is then allowed to cool. reaction and the compound obtained is hydrolyzed. The hydrolysis is carried out in a known manner, preferably in the middle acid. It is preferable to use hydrochloric acid for this purpose.

The (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III obtained after the decomposition of the complex of Grignard can undergo alkylation without purifying the mixture of reaction that contains it. The reaction can be carried out in presence of (+) - unreacted camphor of formula II. However, this leads to the formation of only one small amount of by-products rented because, according to the process of the present invention, formation is suppressed from (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V.

As already mentioned above, the alkylation is carried out in a solvent that does not favor alkylation reaction in position 3 of (+) - camphor of formula II, that is, in a solvent in which the (+) - camphor of formula II is, as maximum, very little rented in position 3. It is particularly it is preferred to use dioxane as an organic solvent because, in a medium containing dioxane, the alkylation of (+) - formula II camphor takes place at most only to a very small degree and, consequently, the amount from (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one   of unwanted formula V in the final product, (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - Bicyclo [2.2.1] heptane of formula I, is small.

The asymmetric centers of (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I in positions 1 and 4 are derived from (+) - 1,7,7-Tri- [methyl] -bicyclo [2.2.1] heptane-2-one, that is, (+) - camphor of formula II.

The alkylation is carried out in the presence of alkali metal amides, for example, amide can be used sodium, or alkali metal hydrides, for example sodium hydride. It is preferred to use sodium amide.

Preferably, it is used as (2- {halogen} -ethyl) -dimethylamine, the (2- {chloro} -ethyl) -dimethylamine.

The metal hydride is used properly alkali or alkali metal amide in an amount of 1 to 3 moles, preferably 1.5 to 2 moles, relative to 1 mole of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III. The amount of alkylating agent is, advantageously, 1.0 to 2.5 moles, preferably 1 to 1.1 moles, in relationship to basic salt forming agent. Preferably, the alkylation reaction of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III with (2- {halogen} -ethyl) -dimethylamine it is carried out under heating, in particular at the point of boiling the reaction mixture. Suitably the reaction It takes place in approximately 3 to 5 hours. A reaction time advantageous is approximately 4 hours.

The (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I can be converted in a pharmaceutically acceptable salt, preferably fumarate, optionally without isolating it from the first. One can proceed, preferably, as follows: of the reaction mixture obtained after alkylation, salts are separated inorganic by filtration at 0-30 ° C, preferably at 20 ° C, whereby the acid pharmaceutically corresponding acceptable, preferably fumaric acid, is added to the filtrate in an approximately equimolar amount (1.0 to 1.5 moles). The crystalline product that precipitates from the medium, such as of the dioxane medium, it is removed by filtration.

Because (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7- tri- [methyl] -bicyclo [2.2.1] heptane of formula I, or pharmaceutically acceptable acid addition salt of it in particular (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2,2,1] heptane fumarate (1: 1) obtained by the procedure according to the invention contains, at most, small amounts of (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V, or pharmaceutically acid addition salts acceptable thereof, respectively, by the procedure of according to the invention can be developed without recrystallization in dimethyl formamide, which, however, only leads to insufficient purification according to known methods, and in Consequently, it does not remove traces of dimethyl formamide from pharmaceutically active principle by methods that are also unsuitable for the proposed purpose. In addition, the latter is a significant progress in view of the impossibility of eliminating dimethyl formamide in sufficient degree due to its high point of boiling, to which (1R, 2S, 4R) - (-) - 2- [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane of formula I se It would decompose.

The advantage of the present procedure invention is that it can be carried out with excellent yields and a high purity product is obtained. In this way, the yield of approximately 46% shown in the Examples is considerably higher than the returns disclosed in the prior art, which do not exceed 25% even if the (+) - camphor is recirculated several times.

The invention is further illustrated by The following Examples. The melting points that occur in the Examples are uncorrected values.

(1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1, 7,7-tri- [methyl] -bicyclo [2.2.1] heptane fumarate (1: 1) [Formula I] Grignard reaction

It is added to a suspension of 48.6 g (1.5 g atom) of magnesium chips and 600 ml of anhydrous tetrahydrofuran, a 20 ml portion of a mixture of 236 g (1.5 moles) of bromine benzene and 200 ml of anhydrous tetrahydrofuran are added at the point boiling Once the Grignard reaction has started, it add the residual part of the bromine benzene mixture to the Drop by drop suspension within one hour. The mixture is heated reaction until boiling until magnesium is completely dissolved. It is added to the Grignard compound, a solution of 152.2 g (1.0 mol) of (+) - camphor of formula II, and 300 ml of anhydrous tetrahydrofuran, under heating constant until boiling, before about half an hour, and the reaction mixture is heated to a boil for a additional period of 5 hours.

Hydrolysis

The reaction mixture is allowed to cool to 25 ° C and is pour over a mixture of 500 ml of heptane, 400 g of ice, 30 g of sodium chloride and 150 ml of concentrated hydrochloric acid under stirring at 0 ° C. The organic phase is separated and basified to pH 10 by adding an aqueous ammonium hydroxide solution 25% weight / volume. After repeated separation, the product is dried and evaporated. vacuum solution. In this way, 220 g of oil are obtained colorless.

Analysis based on the GC

- The test is carried out on a chromatograph of Perkin Elmer Autosystem gases.

- Length 10 m (0.25 mm).

- A capillary column with a fixed phase of 14% cyanopropyl 14% methyl polysiloxane (CPSil-19CB,
Chrompack [Handelsprodukt]).

- The injection is carried out at 200 ° C.

- Heating rate 10ºC / minute.

- Carrier gas: helium.

- Detector: FID, injection temperature 200ºC, final temperature 250 ° C, gas pressure 40 kPa.

Contained in (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2- ol: 66.5%

Content in (+) - camphor: 25%.

Etherification

It is added to a suspension of 45.5 g (1.05 mol) of sodium amide (content: 90% weight / weight) and 500 ml of dioxane anhydrous, a mixture of 200 g of the colorless oil obtained by hydrolysis, which contains (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol, and 100 ml of anhydrous dioxane, at the boiling point before half an hour. The mixture is heated until boiling for 2 hours, after which 113.0 g (1.05 mol) of (2- {chloro} -ethyl) -dimethylamine and the reaction mixture until boiling for an additional period 4 hours

Formation of fumarate salt

The suspension is allowed to cool to 20 ° C, it is filter, and add to the clear filtrate, 121.9 g (1.05 mol) of fumaric acid, under vigorous stirring. The mixture is heated reaction until boiling for 10 minutes, let cool until 15ºC, it is mixed for an additional period of one hour and it filters. The filter crust is washed with dioxane, water and ethanol, and dried at 80 until solvent free. This  way, 190.5 g (0.456 mol) of white crystals are obtained, yield 45.6% [in relation to (+) - camphor]. The melting point of white crystals is between 214 and 216 ° C.

Analysis of the formula C 20 H 31 NO.C 4 H 4 O 4 (417.55) Calculated: C% = 69.03% H% = 8.45% N% = 3.35% Observed: C% = 69.06% H% = 8.42% N% = 3.39%

[α] 20 D = -92.5 ° (c = 0.4, dimethyl sulfoxide, 435 nm).

The product contains less than 0.05% of pollutant (1R, 3S, 4R) -3 - [(2 '- {N, N- dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-one fumarate (1: 1).

Example 2 (Example comparative)

(1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] - bicyclo [2.2.1] heptane fumarate (1: 1) [Formula I] Reproduction of the procedure disclosed in the patent Hungarian No. 212,574 Grignard reaction

To a Grignard compound prepared from 5.52 g (0.23 g atom) of magnesium chips and 36.1 g (0.23 mol) of bromine benzene in 200 ml of anhydrous diethyl ether, a solution of 30.4 g (0.20 moles) of (+) - camphor and 50 ml of anhydrous diethyl ether. The reaction mixture is heated until Boil for 5 hours. The Grignard complex is decomposes by adding an ice cold solution of 20 g of ammonium chloride, the mixture is washed three times with 30 ml of water each time, it is separated, dried over anhydrous magnesium sulfate and the solvent is removed by evaporation. In this way, they are obtained 40.5 g of a colorless oil containing, according to the CG

57.5% from (+) - formula camp II 5.8% from 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol {borneol} 34.5% from (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane- 2-ol of formula III; Y 2.2% of additional contaminants in smaller amounts

Etherification

At a suspension of 3.4 g (67 mmol) of sodium hydride (dispersion of 47.5% weight / weight) and 50 ml of toluene anhydrous, a solution of 40.0 g of the oil obtained in Grignard's reaction, which contains (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol of formula III and 30 ml of anhydrous toluene. The reaction mixture is heats to boil for an hour, after which it add, at the boiling point, a solution of 6.85 g (67 millimoles) of (2- {chloro} -ethyl) -dimethylamine and 10 ml of toluene. The reaction mixture is heated until boiling for a additional period of 4 hours.

Separation

The reaction mixture is washed three times with 25 ml of water each time. The product is extracted with three portions equals a solution of 18 g (0.12 mol) of tartaric acid and 40 ml of water The phases are separated, the aqueous layers are combined, basify to pH 10 with a concentrated solution of hydroxide ammonium, extracted three times with 20 ml of dichloroethane each time, it is dried over magnesium sulfate and the solvent is removed in the empty. In this way, 14.5 g of a colorless oil are obtained which contains, according to the CG analysis

74.2% from (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I; 16.5% from (1R, 4R) -2 - [(2 '- {N, N-dimethylamino} -ethoxy] -1,7,7-tri- [methyl] - bicycles [2.2.1] heptane of formula IV 6.5% from (1R, 3S, 4R) -3 - [(2 '- {N, N-dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-one of formula V; Y some% of contaminants additional unidentified, each in an amount less than 1%.

Formation of fumarate salt

To a solution of 14.0 g of the base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} - ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I, released from the tartrate salt, and 150 ml of ethanol, is 5.07 g (43.6 mmol) of fumaric acid are added at 70 ° C. The product is filtered at 0 ° C and recrystallized from 50 ml of dimethyl formamide

In this way, 13.5 g of the product are obtained desired (1R, 2S, 4R) - (-) - 2 - [(2'- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane  fumarate (1: 1) of formula I in the form of white crystals. Yield 16.2% [in relation to (+) - camphor]. From according to the GC analysis, 0.5% of (1R, 3S, 4R) -3 - [(2 '- {N, N- dimethylamino} -ethyl)] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-one of formula V. Mp .: 214 at 216 ° C.

Analysis of the formula C 20 H 31 NO.C 4 H 4 O 4 (417.55) Calculated: C% = 69.03% H% = 8.45% N% = 3.35% Observed: C% = 69.16% H% = 8.52% N% = 3.32%

Claims (9)

1. Procedure for preparing (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} - ethoxy)] - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula 10 and pharmaceutically acid addition salts acceptable thereof by converting (+) - 1,7,7-Tri- [methyl] -bicyclo [2.2.1] heptane-2-one {(+) - camphor} of formula 8 in (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol from formula 9 by reacting the first with a halide of phenyl magnesium or phenyl alkali compound, if necessary carrying out the hydrolysis of the reaction product, and doing react (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane-2-ol  of formula III obtained in this way with (2- {halogen} -ethyl) -dimethylamine in the presence of a alkali metal hydride or alkali metal amide in a solvent organic and, if desired, turning the base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I obtained in this way in a salt, characterized carrying out the reaction of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [methyl] - bicycle [2.2.1] heptane-2-ol of formula III and (2- {halogen} -ethyl) -dimethylamine in a medium containing 1 or more compounds with a ring 5 or 6-membered saturated heterocyclic with 2 oxygen atoms annular as solvent or solvents 2. Method according to claim 1, characterized in that dioxane is used as the solvent. 3. Method according to claim 1 or 2, characterized in that phenyl magnesium bromide is used as the phenyl magnesium halide. 4. Method according to any one of claims 1 or 2, characterized in that phenyl magnesium chloride is used as the phenyl magnesium halide. 5. Method according to any one of claims 1 to 4, characterized in that 2- (2 '- {chloro} -ethyl) -dimethylamine is used as 2- (2' - {halogen-ethyl) -dimethylamine. Method according to any one of claims 1 to 5, characterized in that the sodium amide is used as an alkali metal amide. Method according to any one of claims 1 to 6, characterized in that the alkylation reaction of (1R, 2S, 4R) - (-) - 2- [phenyl] -1,7,7-tri- [ methyl] -bicyclo [2.2.1] heptane-2-ol of formula III with 2- (2'- {halogen} -ethyl) -dimethylamine under heating, in particular at the boiling point of the reaction mixture. Method according to any one of claims 1 to 7, characterized in that by converting the base (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] -2- [phenyl] -1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I to a salt, salt 2- (E) -butanedioate (1: 1) ( fumarate). Method according to any one of claims 1 to 8, characterized in that the conversion of (1R, 2S, 4R) - (-) - 2 - [(2 '- {N, N-dimethylamino} -ethoxy)] - 2- [phenyl] - 1,7,7-tri- [methyl] -bicyclo [2.2.1] heptane of formula I in salt 2- (E) - butanedioate (1: 1) (fumarate) is carried out without isolation of the first.